Kraepelin initially described involutional melancholia as a distinct clinical entity characterized by late onset, symptoms of fear, despondency, agitation, and hypochondriacal delusions, which formed the basis of the nomenclature in DSM-II. A subsequent report discounted a syndrome of depression at menopause, which served as the basis for the removal of involutional melancholia from DSM-III).1 Sub­sequent findings from the Cross-National Epidemiologic Study indicated an increase in new onsets of depressive illness in the perimenopausal years (women aged 45 to 49). This later work is consistent with a developing database demonstrating an increased risk of MDD occurring in association with hormonal changes during perimenopause.

Increased incidence of MDD at menopause

Many methodological problems, especially of diagnostic and endocrine heterogeneity, characterize studies of menopausal mood disorders. More rigorous studies that use standardized, interview-based assessments of depression in endocrine-defined phases of the menopausal transition support an association between MDD and menopause. In one such study from the NIMH, Schmidt and colleagues2 conducted a longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. The investigators used the Structured Clinical Interview for DSM-IV for assessment of psychiatric diagnoses, and plasma levels of follicle-stimulating hormone, obtained at 3- to 6-month intervals for an average of 5 years, to determine premenopausal, perimenopausal, or postmenopausal status. For the 24 months surrounding women’s final menses, the risk for onset of depression was 14 times higher than for a 31-year premenopausal time period.

Women who had a major depressive episode (MDE) during the perimenopause were not distinguished from those who remained asymptomatic on the basis of symptom profiles; personal or family history of depression; duration of the perimenopause; vasomotor symptoms; life events; medical illness; use of medication, vitamins, or minerals; or exercise. The timing of the depressions, occurring in the context of recently elevated follicle-stimulating hormone levels, suggested that an endocrine mechanism related to the perimenopause (estradiol withdrawal and recent onset of prolonged hypogonadism) was involved in the pathophysiology of perimenopausal depression.

Results of other systematic studies are consistent with these findings. In an 8-year study, Freeman and colleagues3 followed 231 women without depressive histories who were about to enter menopause. Using the Center for Epidemiological Studies of Depression scale, they found that the probability of a high depression score (more than 16) was 4-fold greater during the menopausal transition than during the premenopausal phase. Entering menopause was linked to more than double the risk of a diagnosis for depressive disorder and was associated with within-woman increases in follicle-stimulating hormone and luteinizing hormone levels and greater variability of estradiol and follicle-stimulating hormone levels.

Cohen and colleagues4 also examined the impact of the menopausal transition on depressive symptoms in 460 women without depressive histories, between 36 and 45 years of age. During 3 years of follow-up, the menopausal group, especially women with hot flashes, was twice as likely as the premenopausal group to experience significant depressive symptoms. Major mood disorders occurred in 9.5% of premenopausal and 16.6% of perimenopausal women. These studies used rigorous, standardized criteria for making psychiatric diagnoses. Together, the find-ings lend strong support to the hypothesis of increased vulnerability for an MDE occurring at the time of the menopausal transition.

Clinical phenomenology and epidemiology

According to studies from menopause clinics, the most common symptom for which women seek treatment at menopause is mood change.5 Almost half of these women are clinically depressed and more than a third experience their first episode of depression in the perimenopausal period. Two-thirds of women in London and three-quarters of women in San Diego who were attending a university or community menopause clinic met criteria for recurrent MDD when evaluated by a psychiatric interview.6 Perimenopausal women compared with premenopausal or postmenopausal women had a significant increase in depression rating scores. Mood and sleep disturbances are the most common symptoms in about 75% of women. Depressive episodes also are likely to recur at menopause in women with bipolar illness, and there is an increased number of suicides in women during this time (45 to 64 years).

Studies of past psychiatric histories, including illness related to reproductive endocrine change, of women with menopausal depression support a depressive diathesis at menopause. Women in whom psychiatric symptoms develop in middle age are more likely to evidence psychiatric vulnerability (ie, a previous personal or family psychiatric history). More than half of these women have a past history of depressive disorder. In a 5-year study of 2565 women aged 45 to 55 years, prior depression was the variable most predictive of subsequent depression.7

Psychiatric symptoms at menopause also are related to previous depressions associated with the reproductive cycle, such as premenstrual syndrome (PMS) and depression during pregnancy or the post-partum period. Stewart and Boydell8 found that psychological distress during menopause was associated with a past history of PMS, depressive disorders treated with anti­depressant medication, oral contraceptive–induced dysphorias, post-partum blues, and MDD, suggesting an increased sensitivity to reproductive hormones in these psychiatrically vulnerable women.